High transferability of neutralizing antibodies against SARS-CoV-2 to umbilical cord blood in pregnant women with BNT162b2 XBB.1.5 vaccine - a retrospective cohort study (preprint)

Coronavirus disease 2019 (COVID-19), when contracted by pregnant women, can lead to severe respiratory illness, rapid disease progression, and higher rates of intensive care unit admission. COVID-19 infection during pregnancy is associated with an increased risk of preterm delivery, cesarean section, fetal dysfunction, preeclampsia, and perinatal death. Additionally, vertical transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from pregnant women to their fetuses has been observed. While severe infections in neonates and infants are rare, newborns can experience serious consequences from COVID-19, despite their suboptimal humoral immune system protection. The amino acids in the structural proteins of SARS-CoV-2 are subjected to constant mutation. Since around January 2023, COVID-19, caused by infection with omicron-type SARS-CoV-2 variants, has been prevalent globally. Omicron-type SARS-CoV-2 variants can evade the immune response triggered by traditional mRNA-based COVID-19 vaccines, such as BNT162b2. Therefore, vaccination with a vaccine (BNT162b2 XBB.1.5) that can provide protection against omicron-type SARS-CoV-2 variants is recommended. Therefore, we examined the titers of anti-spike glycoprotein of SARS-CoV-2 IgG and IgA in the blood and umbilical cord blood obtained from pregnant women vaccinated with BNT162b2 XBB.1.5. The results showed that anti-spike glycoprotein of SARS-CoV-2 IgG and IgA titers were highest in the blood and cord blood obtained from pregnant women vaccinated with BNT162b2 XBB.1.5 at late gestational age (28-34 weeks). No serious side effects or adverse events caused by vaccination of pregnant women with BNT162b2 XBB.1.5 were observed in either pregnant women or newborns. In the future, to validate our findings, large cohort clinical studies involving numerous pregnant women must be conducted.

Bilious Emesis and Failure to Pass Meconium in the Nursery: A Case Study.

We present a case of an infant born to a mother with COVID-19, who at 24 hours of life was treated with a glycerin suppository for failure to pass meconium and went on to develop bilious emesis and abdominal distention as feeding continued over the next several hours. After a barium enema identified the distal obstruction, the pediatric surgical team used rectal irrigation to remove a large meconium plug, which mimicked the appearance of the descending colon on plain film, in a case of small left colon syndrome. Although intestinal obstruction in the newborn is rare, it is imperative that it is promptly diagnosed and treated appropriately to avoid negative outcomes; which, even in perhaps the mildest form of functional distal obstruction, meconium plug syndrome, can lead to an impressive clinical illness with risk of intestinal perforation and subsequent meconium peritonitis if the obstruction is not relieved.

COVID-19 Vaccines: The Impact on Pregnancy Outcomes and Menstrual Function (preprint)

Objectives Assess rates of adverse events (AE) after COVID-19 vaccines experienced by women of reproductive age, focusing on pregnancy and menstruation, using data collected by the US Centers for Disease Control and Prevention (CDC) Vaccine Adverse Events Reporting System (VAERS) database. Design Population-based retrospective cohort study. Setting US and global entries in US Centers for Disease Control and Prevention (CDC) Vaccine Adverse Events Reporting System (VAERS). Participants CDC VAERS entries from January 1, 1998 to June 30, 2022. Interventions None. Main Outcome Measures A proportional reporting ratio analysis is performed using data in the VAERS system comparing adverse events (AE) reported post-COVID-19 vaccines with that of post-Influenza vaccines. Results COVID-19 vaccines, when compared to the Influenza vaccines, are associated with a significant increase in AE with all proportional reporting ratios of > 2.0: menstrual abnormalities, miscarriage, fetal chromosomal abnormalities, fetal malformation, fetal cystic hygroma, fetal cardiac disorders, fetal arrhythmias, fetal cardiac arrest, fetal vascular malperfusion, fetal growth abnormalities, fetal abnormal surveillance, fetal placental thrombosis, low amniotic fluid, preeclampsia, premature delivery, preterm premature rupture of membrane, fetal death/stillbirth, and premature baby death (all p values were much smaller than 0.05). When normalized by time-available, doses-given, or persons-received, all COVID-19 vaccine AE far exceed the safety signal on all recognized thresholds. Conclusions Pregnancy complications and menstrual abnormalities are significantly more frequent following COVID-19 vaccinations than Influenza vaccinations. A worldwide moratorium on the use of COVID-19 vaccines in pregnancy is advised until randomized prospective trials document safety in pregnancy and long-term follow-up in offspring.

Accessing termination of pregnancy due to fetal anomaly during COVID-19 in South Australia: A qualitative case study (preprint)

Objective: Examine experiences of termination of pregnancy (TOP) in South Australia to recommend areas for service improvement following decriminalisation legislation. Design Qualitative case study. Setting Online semi-structured interview. Participants The case study was an example of the unheard, complex and distressing circumstance of TOP due to fetal anomaly diagnosis. The case was selected from larger sample (N=8) of adults who had recently had a TOP in South Australia as a subgroup from a larger study looking at the potential missed opportunities of health professionals to provide access to contraception prior to abortion. Methods Semi-structured, in depth, qualitative interview. Qualitative description using thematic content analysis identified significant aspects of the participant’s story pertaining to potential health service improvements. Results The participant experienced trauma navigating a difficult care pathway following a diagnosis of fetal anomaly. They described inadequacy of labels for pregnancy such as planned, unplanned, wanted, unwanted, the framing of abortion through the lens of ‘choice’, and confusion about service referrals and inappropriate communication by health professionals. Not being able to have a partner accompany her through the process of having a TOP due to COVID-19 restrictions resulted in extreme distress. Conclusion Abortion services need clear care pathways that are context specific, and patient centred. The language and attitudes of health professionals can result in distressing experiences of TOP. Further investigation of the relationship between infection control strategies and trauma in health service provision is warranted to improve future pandemic responses.

Congenital Infection of Severe Acute Respiratory Syndrome Coronavirus 2 With Intrauterine Fetal Death: A Clinicopathological Study With Molecular Analysis.

BACKGROUND: Observations of vertical transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from mother to fetus have recently been described in the literature. However, the consequences of such transmission, whether fetal or neonatal, are poorly understood. METHODS: From a case of in utero fetal death at 24+2 weeks of gestation that occurred 7 days after the diagnosis of symptomatic SARS-CoV-2 infection in the mother, we isolated the incriminating virus by immunochemistry and molecular techniques in several fetal tissues, with a variant analysis of the SARS-CoV-2 genome. RESULTS: The fetal demise could be explained by the presence of placental histological lesions, such as histiocytic intervillositis and trophoblastic necrosis, in addition to fetal tissue damage. We observed mild fetal growth retardation and visceral damage to the liver, causing hepatocellular damage and hemosiderosis. To the best of our knowledge, this is the first report in the literature of fetal demise secondary to maternal-fetal transmission of SARSCoV- 2 with a congenital infection and a pathological description of placental and fetal tissue damage. CONCLUSIONS: SARS-CoV-2 was identified in both specimens using 3 independent techniques (immunochemistry, real-time quantitative polymerase chain reaction, and realtime digital polymerase chain reaction). Furthermore, the incriminating variant has been identified.

Parvovirus (B19) Infection during Pregnancy: Possible Effect on the Course of Pregnancy and Rare Fetal Outcomes. A Case Report and Literature Review.

Infection caused by human parvovirus B19 (B19) often has mild yet wide-ranging clinical signs, with the course of disease usually defined as benign. Particularly prevalent in the population of young children, the virus is commonly transmitted to the parents, especially to susceptible mothers. During pregnancy, particularly the first and second trimesters, parvovirus infection can lead to pathology of the fetus: anemia, heart failure, hydrops, and disorders of physical and neurological development. In severe cases, the disease can result in fetal demise. This article presents a rare case of manifestation of B19 infection during pregnancy. At the 27th week of gestation, a sudden change in fetal movement occurred in a previously healthy pregnancy. The examination of both fetus and the mother revealed newly formed fetal subdural hematoma of unknown etiology and ventriculomegaly. Following extensive examination to ascertain the origin of fetal pathology, a maternal B19 infection was detected. Due to worsening fetal condition, a planned cesarean section was performed to terminate the pregnancy at 31 weeks of gestation. A preterm male newborn was delivered in a critical condition with congenital B19 infection, hydrocephalus, and severe progressive encephalopathy. The manifestation and the origin of the fetal condition remain partially unclear. The transplacental transmission of maternal B19 infection to the fetus occurs in approximately 30% of cases. The main method for diagnosing B19 infection is Polymerase Chain Reaction (PCR) performed on blood serum. In the absence of clinical manifestations, the early diagnosis of B19 infection is rarely achieved. As a result, the disease left untreated can progress inconspicuously and cause serious complications. Treatment strategies are limited and depend on the condition of the pregnant woman and the fetus. When applicable, intrauterine blood transfusion reduces the risk of fetal mortality. It is crucial to assess the predisposing factors of the infection and evaluate signs of early manifestation, as this may help prevent the progression and poor outcomes of the disease.

The Term Newborn: Congenital Infections.

Maternal pathogens can be transmitted to the fetus resulting in congenital infection with sequelae ranging from asymptomatic infection to severe debilitating disease and still birth. The TORCH pneumonic (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus) is used widely, but it provides a limited description of the expanding list of pathogens associated with congenital infection. This article focuses on the evaluation and management of infants with common congenital infections such as cytomegalovirus, and infections that warrant early diagnosis and treatment to prevent serious complications, such as toxoplasmosis, human immunodeficiency virus, and syphilis. Zika virus and Chagas disease remain uncommon.

No evidence of fetal defects or anti-syncytin-1 antibody induction following COVID-19 mRNA vaccination (preprint)

The impact of coronavirus disease 2019 (COVID-19) mRNA vaccination on pregnancy and fertility has become a major topic of public interest. We investigated two of the most widely propagated claims to determine 1) whether COVID-19 mRNA vaccination of mice during early pregnancy is associated with an increased incidence of birth defects or growth abnormalities, and 2) whether COVID-19 mRNA-vaccinated human volunteers exhibit elevated levels of antibodies to the human placental protein syncytin-1. Using a mouse model, we found that intramuscular COVID-19 mRNA vaccination during early pregnancy at gestational age E7.5 did not lead to differences in fetal size by crown-rump length or weight at term, nor did we observe any gross birth defects. In contrast, injection of the TLR3 agonist and double-stranded RNA mimic polyinosinic-polycytidylic acid, or poly(I:C), impacted growth in utero leading to reduced fetal size. No overt maternal illness following either vaccination or poly(I:C) exposure was observed. We also found that term fetuses from vaccinated murine pregnancies exhibit high circulating levels of anti-Spike and anti-RBD antibodies to SARS-CoV-2 consistent with maternal antibody status, indicating transplacental transfer. Finally, we did not detect increased levels of circulating anti-syncytin-1 antibodies in a cohort of COVID-19 vaccinated adults compared to unvaccinated adults by ELISA. Our findings contradict popular claims associating COVID-19 mRNA vaccination with infertility and adverse neonatal outcomes.

Comprehensive Serological Profile and Specificity of Maternal and Neonatal Cord Blood SARS CoV-2 Antibodies (preprint)

ObjectiveTo describe the profile and specificity of maternal and neonatal cord-blood antibody profile in response SARS-CoV-2 virus exposure MethodsThis is a Prospective cohort study of delivering patients at Thomas Jefferson University Hospital from April 2020-February 2021. Primary objective was to describe unique maternal and fetal antibody epitope titers and specificity in those patients with COVID-19 history. Serologic profile assessed with a multiplex platform. Antigens used were: HA-trimer Influenza A (Hong Kong H3), spike trimers for SARS-CoV-2, SARS-CoV-1, MERS-CoV, and betacoronaviruses HKU-1 and OC43, as well as the spike N-terminal domain (NTD), spike receptor binding domain (RBD), and nucleocapsid protein (N; full length) for SARS-CoV-2. Results112 maternal samples and 101 maternal and cord blood pairs were analyzed. Thirty-seven had a known history of COVID-19 (positive PCR test) in the pregnancy and of those, 17 (47%) were diagnosed with COVID-19 within 30 days of delivery. Fifteen of remaining seventy-six (20%) without a known diagnosis had positive maternal serology. For those with history of COVID-19 we identified robust IgG response in maternal blood to CoV2 nucleocapsid (N), spike (S) full-length and S (RBD) antigens with more modest responses to the S (NTD) antigen. By contrast, the maternal blood IgM response appeared more specific to S (full-length), than N, S (RBD) or S (NTD) epitopes. There were significantly higher maternal and cord blood IgG response not just to CoV2 spike (p < 10-18), but also CoV1 spike (p < 10-9) and MERS spike (p < 10-8). By contrast, maternal IgM responses were more specific to CoV2 (p < 10-19), but to a lesser degree for CoV1 (p < 10-5), and no significant differences for MERS. Maternal and cord-blood IgG were highly correlated for both S and N (R2 = 0.96 and 0.94). ConclusionsPlacental transfer is efficient, with robust N and S responses. Both nucleocapsid and spike antibody responses should be studied for a better understanding of COVID-19 immunity. IgG antibodies are cross reactive with related CoV-1 and MERS spike epitopes while IgM, which cannot cross placenta to provide neonatal passive immunity, is more SARS CoV-2 specific. Neonatal cord blood may have significantly different fine-specificity than maternal blood, despite the high efficiency of IgG transfer.

Aortic thrombosis in a neonate with COVID-19-related fetal inflammatory response syndrome requiring amputation of the leg: a case report.

Neonatal infection with SARS-CoV-2 is considered to have no major complications. A neonate with lower limb gangrene owing to spontaneous aortic thrombosis in the setting of a fetal inflammatory response syndrome (FIRS) post-intrauterine COVID-19 infection is presented. A healthy full-term newborn discharged from hospital on Day 3 developed irritability and progressive blackish discoloration of the toes of the right lower limb on Day 6 of life. Doppler imaging revealed acute thrombosis of the abdominal aorta with a critically ischaemic right lower limb. On Day 11 of life, SARS-CoV-2 RT-PCR was negative but total antibodies (IgG and IgM) were positive in both mother and neonate. The neonate showed raised inflammatory markers including CRP, ESR, interleukin-6, procalcitonin, ferritin and LDH along with elevated N-terminal pro-brain natriuretic peptide and D-dimer. In the absence of clinical signs of sepsis, FIRS was diagnosed. The neonate was treated with corticosteroids, heparin infusion and recombinant tissue plasminogen activator, and required surgical embolectomy followed by right limb amputation. By Day 31 of life, inflammatory markers showed serial return to normal and the neonate was discharged on oral steroids and aspirin. Intrauterine SARS-CoV-2 infection may trigger a systemic inflammatory response in some fetuses which is similar to post-COVID-19 multisystem inflammatory syndrome in children (MIS-C). Development of lower limb gangrene is a unique COVID-19-related neonatal complication and is attributed to thrombo-inflammation.ABBREVIATIONSCRP: C-reactive protein; FIRS: fetal inflammatory response syndrome; MIS-C: multisystem inflammatory syndrome in children; NT-proBNP: N-terminal pro-brain natriuretic peptide; RT-PCR: real-time polymerase chain reaction.

Evaluation of vertical transmission of SARS-CoV-2 in utero: Nine pregnant women and their newborns.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), mainly transmitted by droplets and close contact, has caused a pandemic worldwide as of March 2020. According to the current case reports and cohort studies, the symptoms of pregnant women infected with SARS-CoV-2 were similar to normal adults and may cause a series of adverse consequences of pregnancy (placental abruption, fetal distress, epilepsy during pregnancy, etc.). However, whether SARS-CoV-2 can be transmitted to the fetus through the placental barrier is still a focus of debate. METHODS: In this study, in order to find out whether SARS-CoV-2 can infect fetus through the placental barrier, we performed qualitative detection of virus structural protein (spike protein and nucleoprotein) and targeted receptor protein Angiotensin Converting Enzyme 2 (ACE2), Basigin (CD147) and molecular chaperone GRP78 expression on the placental tissue of seven pregnant women diagnosed with COVID-19 through immunohistochemistry. Amniotic fluid, neonatal throat, anal swab and breastmilk samples were collected immediately in the operating room or delivery room for verification after delivery, which were all tested for SARS-CoV-2 by reverse transcriptionpolymerase chain reaction (RT-PCR). RESULTS/DISCUSSION: The result showed that CD147 was expressed on the basal side of the chorionic trophoblast cell membrane and ACE2 was expressed on the maternal side, while GRP78 was strongly expressed in the cell membrane and cytoplasm. The RT-PCR results of Amniotic fluid, neonatal throat, anal swab and breastmilk samples were all negative. On the basis of these findings, we speculated that it may be due to the placental barrier between mother and baby, for example, villous matrix and interstitial blood vessels have low expression of virus-related receptors (ACE2, CD147, GRP78), the probability of vertical transmission of SARS-CoV-2 through the placenta is low.

Microphthalmia and Optic Nerve Hypoplasia Induced by Maternal Coronavirus Infection? (preprint)

Possible mother-to-child transmission of severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) during pregnancy is still a matter of debate. We studied the impact of SARS-CoV-2 infection on 56 complete households, including 27 newborns whose mothers were pregnant when exposed to the virus. Three perinatal SARS-CoV-2 transmissions with mild symptoms in affected neonates were recorded (two cases confirmed by PCR, the third one based on clinical findings). In addition, we observed a severe eye malformation (unilateral microphthalmia, optic nerve hypoplasia, and congenital retinopathy) associated with maternal SARS-CoV-2 infection in weeks 5 and 6 of embryonic development. This embryopathy could not be explained by other infectious agents, genetic factors, or drug use during pregnancy. Eight other women with a history of SARS-CoV-2 infection prior to gestational week 12, however, delivered healthy infants.Conclusion: The repeated occurrence of mother-to-child transmission in our cohort with risks that remain incompletely understood, such as long-term effects and the possibility of an embryopathy, should sensitize researchers and stimulate further studies as well as strongly support COVID19 vaccination recommendations for pregnant women.Trial registration number: NCT04741412Date of registration: November 18, 2020

Increased placental expression of angiotensin-converting enzyme 2, the receptor of SARS-CoV-2, associated with hypoxia in twin anemia-polycythemia sequence (TAPS).

INTRODUCTION: Recent reports suggest SARS-CoV-2, the virus causing COVID-19, may be transmittable from pregnant mother to placenta and fetus, albeit rarely. The efficacy of vertical transmission of SARS-CoV-2 critically depends on the availability of its receptor, ACE2, in the placenta. In the present study, we tested the hypothesis that placental ACE2 expression is oxygenation-dependent by studying the expression of ACE2 and associated cell entry regulators in the monochorionic twin anemia-polycythemia (TAPS) placenta, a model of discordant placental oxygenation. METHODS: We performed a retrospective comparative immunohistochemical, immunofluorescence and Western blot analysis of ACE2, TMPRSS2 and Cathepsin B expression in anemic and polycythemic territories of TAPS placentas (N = 14). RESULTS: ACE2 protein levels were significantly higher in the anemic twin territories than in the corresponding polycythemic territories, associated with upregulation of the key ACE2-related cell entry regulators, TMPRSS2 and Cathepsin B, immunolocalized to villous trophoblastic and stromal cells. Cellular colocalization of ACE2 and TMPRSS2, suggestive of functionality of this cell entry axis, was demonstrated by double immunofluorescence studies. DISCUSSION: Placental hypoxia is associated with upregulation of ACE2 expression, concomitant with increased expression of its key cell entry proteases. ACE2-regulated placental functions, both infection- and non-infection related, may be highly oxygenation-dependent.

Impact of SARS-CoV-2 (COVID-19) on pregnancy: a systematic review and meta-analysis protocol.

INTRODUCTION: The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has been growing at an accelerating rate, and has become a public health emergency. Pregnant women and their fetuses are susceptible to viral infection, and outcomes in this population need to be investigated. METHODS AND ANALYSIS: PubMed, Web of Science, Embase, CINAHAL, Latin American and Caribbean Health Sciences Literature, clinicaltrials.gov, SCOPUS, Google Scholar and Cochrane Central Controlled Trials Registry will be searched for observational studies (cohort and control cases) published from December 2019 to present. This systematic review and meta-analysis will include studies of pregnant women at any gestational stage diagnosed with COVID-19. The primary outcomes will be maternal and foetal morbidity and mortality. Three independent reviewers will select the studies and extract data from the original publications. The risk of bias will be assessed using the Newcastle-Ottawa Scale for observational studies. To evaluate the strength of evidence from the included data, we will use Grading of Recommendation Assessment, Development, and Evaluation method. Data synthesis will be performed using Review Manager software V.5.2.3. To assess heterogeneity, we will compute the I2 statistics. Additionally, a quantitative synthesis will be performed if the included studies are sufficiently homogenous. ETHICS AND DISSEMINATION: This study will be a review of the published data, and thus it is not necessary to obtain ethical approval. The findings of this systematic review will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: PROSPERO 2020: CRD42020181519.

Fetal Inflammatory Response Syndrome Associated With Maternal SARS-CoV-2 Infection.

Amid the coronavirus disease 2019 pandemic, uncertainty exists about the potential for vertical transmission from mothers infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the fetus in utero. In this case report, we aim to demonstrate the occurrence of a fetal inflammatory response syndrome associated with maternal SARS-CoV-2 infection resulting in neonatal morbidity. In this report we describe an infant of a SARS-CoV-2-positive mother born prematurely with late-onset fever, thrombocytopenia, and elevated levels of inflammatory markers, all of which are consistent with a systemic inflammatory response. The neonate was tested for SARS-CoV-2 by using 2 nasopharyngeal swabs 24 hours apart, and results of both were negative. The result of a full workup for additional infectious pathogens was also negative. Although initially in critical condition in the perinatal period, the infant recovered completely before discharge. We hypothesize that this systemic inflammation occurred in response to maternal viral infection in the absence of vertical transmission of the virus. During the coronavirus disease 2019 pandemic, it will be important to consider the virus as a nidus for a fetal inflammatory response syndrome and resulting morbidity, even in the setting of a negative SARS-CoV-2 testing result in the infant.

Single-cell expression profiles of ACE2 and TMPRSS2 reveals potential vertical transmission and fetus infection of SARS-CoV-2.

Morbidity and mortality of coronavirus disease 2019 (COVID-19) is age-dependent. It remains unclear whether vertical severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurs during pregnancy and how such infection will affect fetal development. Here, we performed single-cell transcriptomic analysis of placenta and other tissues from fetuses in comparison with those from adults using public-available datasets. Our analysis revealed that a very small proportion of trophoblast cells expressed the Angiotensin I Converting Enzyme 2 (ACE2) gene, suggesting a low possibility of vertical transmission of SARS-CoV-2 from mother to fetus during pregnancy. We found that the fetal adrenal gland, heart, kidney and stomach were susceptible to SARS-CoV-2 infection, because these organs contained cell clusters that expressed high levels of the ACE2 gene. In particular, a higher proportion of ACE2-expressing cell clusters in the adrenal gland and kidney also expressed the Transmembrane Serine Protease 2 (TMPRSS2) gene compared with other organs. Surprisingly, ACE2-expressing type II alveolar (AT2) equivalent cells were absent in fetal lungs. This is in sharp contrast to adult lungs. As ACE2 expression is regulated by various conditions, including oxygen concentration, inflammation and smoking, caution is warranted to avoid triggering potential ACE2 expression in fetal and placental tissue.